Oral drug administration is the most common drug delivery route. Typically, it is desirable that the drug is delivered at a controlled rate from the gastrointestinal tract to maintain a controlled level of the drug in the blood stream and the tissue. Further, controlled drug delivery is needed to control diurnal variations that may result from oral intake by a patient at specific times during the day. Yet, the degree to which the drug is available to the target tissue is affected by drug dissolution, drug degradation in the gastrointestinal tract, and drug absorption. This degree is referred to as bioavailability of orally administered drugs and is generally not constant with time. Some drugs have high bioavailability and may be dissolved and absorbed too fast, so as to peak shortly after intake. In these cases, controlled release dosage forms may be utilized that attempt to slow down the dissolution process. Some drugs have very low bioavailability and may be eliminated by the gastrointestinal tract before they are absorbed. In these cases, approaches that increase absorption and approaches that increase gastrointestinal retention may be employed.
The absorption of a drug (or of a drug precursor) into the systemic circulation is determined by the physicochemical properties, its formulations, and the route of administration of the drug. The route of administration may be oral, rectal, topical, by inhalation, or by intravenous administration. Oral administration includes swallowing, chewing, sucking, as well as buccal administration, i.e., placing a drug between the gums and cheek, and sublingual administration, i.e., placing a drug under the tongue. The advantage of chewing, sucking, as well as buccal and sublingual administration is that they lead to direct absorption via the oral cavity, where oral cavity additionally provide a route that avoids both the gastrointestinal tract and its losses, and the presystemic, first-pass metabolism, in the liver.
A prerequisite to absorption of the drug is the dissolution of drug. Typically, the extent of drug dissolution depends on whether the drug is in salt, crystal, or hydrate form. To improve the dissolution, disintegrants and other excipients, such as diluents, lubricants, surfactants (substances which increase the dissolution rate by increasing the wet-ability, solubility, and dispersibility of the drug), binders, or dispersants are often added during manufacture of the drugs.
Numerous gastrointestinal secretions, low pH values, and degrading enzymes may account to drug degradation in the gastrointestinal tract. Since luminal pH varies along the gastrointestinal tract, the drug must withstand different pH values. Further, interaction with blood, food stuff, mucus, and bile may also affect the drug. Reactions that may affect the drug, and reduce bioavailability are complex formations, for example, between tetracycline and polyvalent metal ions, hydrolysis by gastric acid or digestive enzymes, for example, penicillin and chloramphenicol palmitatehydrolysis. Further the complex formations may be conjugation in the gut wall, for example, sulfo-conjugation of isoproterenol or adsorption to other drugs, for example, digoxin and cholestyramine, and metabolism by luminal microflora.
Overall, low bioavailability is most common with oral dosage forms of poorly water-soluble and, slowly absorbed drugs. Insufficient time in the gastrointestinal tract is another common cause of low bioavailability. Ingested drug is exposed to the entire gastrointestinal tract for no more than 1 to 2 days and to the small intestine for only 2 to 4 hours. If the drug does not dissolve readily or cannot penetrate the epithelial membrane quickly, its bioavailability will be low. Moreover, age, sex, activity, genetic phenotype, stress, disease (e.g., achlorhydria, malabsorption syndromes), or previous GI surgery of the patient may also affect drug bioavailability.
Table 1 below [Encyclopedia of Controlled Drug Delivery, volume 2, edited by Edith Mathiowitz] summarizes some parameters of the oral route that affect drug bioavailability:
TABLE 1LIQUIDSECRE-TRANSITAREA,TION,PHTIME,SECTIONM2LITER/DAYVALUEHOUROral~0.050.5-2  5.2-6.8ShortcavityStomach0.1-0.22-41.2-3.51-2Duodenum~0.041-24.6-6.01-2Small45000.24.7-6.5 1-10Intestine(includingmicrovillies)Large0.5-1  ~0.27.5-8.0 4-20Intestine
In addition to the physical barrier of the epithelial cells, chemical and enzymatic barriers also affect drug absorption. Another important barrier to drug absorption is the presystemic, first-pass metabolism, primarily hepatic metabolism. The predominant enzymes in this metabolism are the multi-gene families of cytochrome P450, which have a central role in metabolizing drugs. It appears that variations in P450s between individuals lead to variations in their ability to metabolize the same drug.
Additionally, Multidrug Resistance (MDR) may be a barrier to drug absorption. MDR, which is a major cause of cancer treatment failure, is a phenomenon whereby cancer cells develop a broad resistance to a wide variety of chemotherapeutic drugs. MDR has been associated with over-expression of P-glycoprotein (P-gp) or Multidrug Resistance-associated Protein (MRP), which are transmembrane transporter molecules that act as pumps to remove toxic drugs from tumor cells. P-glycoprotein acts as a unidirectional efflux pump in the membrane of Acute Myelogenous Leukemia (AML) cells and lowers the intracellular concentration of cytotoxic agents, by pumping them out of leukemic cells. However, P-glycoprotein confers resistance to a variety of chemotherapy drugs, including daunorubicin.
Various approaches are available for increased drug absorption. Except for the route of intravenous administration, after dissolution, a drug must traverse several semi permeable biologic barriers before reaching the systemic circulation. A drug may cross the biologic barrier by passive diffusion, or by other naturally occurring transfer modes, for example, facilitated passive diffusion, active transport, or pinocytosis. Alternatively, a drug may be artificially assisted to cross the biologic barrier.
In passive diffusion, transport depends on the concentration gradient of the solute across the biologic barriers. Since the drug molecules are rapidly removed by the systemic circulation, drug concentration in the blood is low compared with that at the administration site, producing a large concentration gradient. The drug diffusion rate is directly proportional to that gradient. The drug diffusion rate also depends on other parameters, for example, the molecule's lipid solubility and size. Lipid-soluble drugs diffuse more rapidly through cell membranes than relatively lipid-insoluble drugs, because cell membranes are lipoid. Further, small drug molecules penetrate biologic barriers more rapidly than large ones.
Another naturally occurring transfer mode is facilitated passive diffusion, which occurs for certain molecules, such as glucose. It is believed that a carrier component combines reversibly with a substrate molecule at the cell membrane exterior. The carrier-substrate complex diffuses rapidly across the membrane, releasing the substrate at the interior surface. This process is characterized by selectivity and saturability: the carrier is operative only for substrates with a relatively specific molecular configuration, and the process is limited by the availability of carriers.
An alternative is nanotechnology, which derives its name from the size of the objects that it deals with. The size of these objects is usually smaller than 100 nanometers, and may even be at the molecular scale. As related to pharmaceuticals, the drugs particle are reduced to “nano” size, for smoother release, better dissolution pattern, better control on absorption, and decreasing the required dose.
Active transport, which is another naturally occurring transfer mode, appears to be limited to drugs that are structurally similar to endogenous substances. Active transport is characterized by selectivity and saturability and requires energy expenditure by the cell. It has been identified for various ions, vitamins, sugars, and amino acids.
Still another naturally occurring transfer mode is pinocytosis, in which fluids or particles are engulfed by a cell. The cell membrane encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior. Like active transport, this mechanism requires energy expenditure. It is known to play a role in drug transport of protein drugs.
The foregoing discussion relates to naturally occurring transfer modes. Where these are insufficient, for example, in cases of macromolecules and polar compounds, which cannot effectively traverse the biological barrier, drug transport may be artificially induced.
Electro transport refers generally to electrically induced passage of a drug (or a drug precursor) through a biological barrier. Several electrotransport mechanisms are known. Iontophoresis involves the electrically induced transport of charged ions, by the application of low level, direct current (DC) to a solution of the medication. Since like electrical charges repel, the application of a positive current drives positively charged drug molecules away from the electrode and into the tissues; similarly, a negative current will drive negatively charge ions into the tissues. Iontophoresis is an effective and rapid method of delivering water-soluble, ionized medication. Where the drug molecule itself is not water-soluble, it may be coated by some water soluble entities. For example, the coating may be of Sodium Lauryl Sulfate (SLS), that may form, water soluble entities. Electroosmosis involves the movement of a solvent with the agent through a membrane under the influence of an electric field. Electrophoresis is based on migration of charged species in an electromagnetic field. Ions, molecules, and particles with charge carry current in solutions when an electromagnetic field is imposed. Movement of a charged species tends to be toward the electrode of opposite charge. The voltages for continuous electrophoresis is are rather high (several hundred volts). Electroporation is the process in which a biological barrier is subjected to a high voltage alternating-current (AC) surge, or pulse. The AC pulse creates temporary pores in the biological membrane, specifically between cells. The pores allow large molecules, such as proteins, Deoxyribonucleic Acid (DNA), Ribonucleic Acid (RNA), and plasmids to pass through the biological barrier. Iontophoresis, electroosmosis, and electrophoresis are diffusion processes, in which diffusion is enhanced by electrical or electromagnetic driving forces. In contrast, electroporation literally punctures the biological barriers, along cell boundaries, enabling a through passage of large molecules.
Generally a combination of more than one of the above-discussed processes is at work, together with passive diffusion and other naturally occurring transfer modes. Therefore, electrotransport refers to at least one, and possibly a combination of the aforementioned transport mechanisms, which supplement the naturally occurring transfer modes.
U.S. Pat. No. 5,298,017, to Theeuwes, et al., entitled “Layered electrotransport drug delivery system,” describes an iontophoretic agent delivery device, having a layered structure and peripheral insulation, wherein ion transport occurs through two opposing surfaces of said device. The device is especially suited to agent delivery through body surfaces exposed to body fluids. U.S. Pat. No. 6,006,130, to Higo, et al., entitled “Iontophoresis electrode and iontophoresis device using the electrode”, describes an iontophoresis electrode that is applicable to mucous membranes and oral mucous membranes, and especially capable of sticking directly on human oral mucous membranes and hence, administering medicine.
Other medical devices that include drug delivery by electrotransport are described, for example, in U.S. Pat. No. 5,674,196, to Donaldson, et al., U.S. Pat. No. 5,961,482, to Chien, et al., U.S. Pat. No. 5,983,131, to Weaver, et al., U.S. Pat. No. 5,983,134, to Ostrow, and U.S. Pat. No. 6,477,410, to Henley, et al., all of whose disclosures are incorporated herein by reference.
In addition to the aforementioned electrotransport processes, there are other electrically assisted drug delivery mechanisms, as follows:
Sonophoresis, or the application of ultrasound, induces growth and oscillations of air pockets, a phenomenon known as cavitation. This disorganizes lipid bilayers thereby enhancing transport. For effective drug transport, a low frequency of between 20 kHz and less than 1 MHz, rather than the therapeutic frequency, should be used. For example, U.S. Pat. No. 5,458,140, to Eppstein, et al., entitled “Enhancement of transdermal monitoring applications with ultrasound and chemical enhancers”, describes a method of enhancing the permeability of the skin or mucosa to an analyte for diagnostic purpose utilizing ultrasound or ultrasound together with a chemical enhancer. The concentration of an analyte in the body is preferably determined by enhancing the permeability of the skin or other biological membrane optionally with a chemical enhancer, applying ultrasound optionally at a modulated frequency, amplitude, phase, or combinations thereof that further induces a local pressure gradient out of the body. Next, collecting the analyte, and utilizing the analyte collection data for calculating the concentration of the analyte in the body.
Other sonophoresis devices are described, for example, in U.S. Pat. Nos. 6,002,961 and 6,018,678 to Mitragotri, et al., U.S. Pat. Nos. 6,190,315 and 6,041,253 to Kost, et al., U.S. Pat. No. 5,947,921 to Johnson, et al. and U.S. Pat. Nos. 6,491,657, and 6,234,990 to Rowe, et al., all of whose disclosures are incorporated herein by reference.
Ablation, or the literal slicing of tissue, by various means, is another method of forcing drugs through a biological barrier. In addition to mechanical ablation, for example with hyperdemic needles, one may use laser ablation, cryogenic ablation, thermal ablation, microwave ablation, radio frequency ablation or electrical ablation. In essence, electrical ablation is similar to electroporation, but tends to be more severe.
U.S. Pat. No. 6,471,696, to Berube, et al., describes a microwave ablation catheter, which may be used as a drug delivery device. U.S. Pat. No. 6,443,945, to Marchitto, et al., describes a device for pharmaceutical delivery using laser ablation. U.S. Pat. No. 4,869,248, to Narula describes a catheter for performing localized thermal ablation, for purposes of drug administration. U.S. Pat. Nos. 6,148,232 and 5,983,135, to Avrahami, describe drug delivery systems by electrical ablation. The disclosures of all of these are incorporated herein by reference.
Various controlled release dosage forms are known. Oral controlled-release dosage forms are often designed to maintain therapeutic drug concentrations for at least 12 hours. Several controlled release mechanisms may be used, for example, as taught by Encyclopedia of Controlled Drug Delivery, volume 2, edited by Edith Mathiowitz, pp. 838-841. These are based on the use of specific substances, generally polymers, as a matrix or as a coating. These may be materials that degrade fast or slowly, depending on the desired effect. For example, when a drug's half-life in the body is too short, the drug may be coated with a slowly dissolving coating. Consequently, the drug must diffuse through the coating, which slows down (or increases) its half-life. Other coating materials form pores that fill with gastrointestinal fluids, increase the contact area between the drug and the gastrointestinal fluids, and reduce the diffusion path in the drug matrix, so as to increase the drug half-life. In these and other manners, modified forms of drug release prolong, delay or sustain the release of a drug in a passive, controlled manner, wherein passive refers to systems not controlled by electronics.
Modified drug release forms, for passive, controlled release include osmotic systems, membrane-coated tablets, enteric-coated dosage forms, multilayered tablets, pH independent controlled release tablets, a hydrogel plug dosage form, multiparticulate dosage forms, and the like. Osmotic systems rely on the uptake of water by the dosage form to increase the osmotic pressure within the system. The build-up of osmotic pressure drives the drug through an orifice in the dosage form to release the drug in a controlled manner. Membrane-coated tablets consist of water-soluble drug particles compressed to form a tablet core. A coating of a substantially insoluble polymer, for example, polyvinyl chloride, is applied to the tablet core, wherein the coating is mixed with a water soluble, pore-forming compound. Additionally, the solubility of the pore-forming compound may be pH dependent, to target a specific zone in the gastrointestinal tract. The rate of drug release is dependent on the pH level and on the extent of porosity in the coating, after the pores are formed. Enteric-coated dosage forms are dosage forms in which a drug core is coated with a polymeric mixture, formed of soluble and insoluble particles. The soluble particles dissolve in the intestinal fluids, exposing the insoluble particles. As a result, a micro porous layer is formed around the drug core and the drug slowly permeates through the pores.
Multilayered tablets consist of a drug core layered with several coatings, which may be of different solubilities, to provide release of drug at specific time intervals and (or) pH levels. As each layer dissolves, a pulsatile-type release is achieved. By modifying the types and amount of polymers used in the several coatings, the release rate may be adjusted. pH independent controlled release tablets are produced by wet granulating an acidic or basic drug blend with a buffering agent and appropriate excipients. The granules are then coated with, a film, which is permeable to gastrointestinal fluid, and the coated composite is compressed into a tablet. Upon oral administration, gastrointestinal fluid permeates the film coating. When in contact with the gastrointestinal fluid, the buffering agents adjust the pH value of the tablet; the drug dissolves and permeates out at a constant rate, independent of the pH level in the gastrointestinal tract. Hydrogel plug dosage form consists of a capsule having a water insoluble body sealed with a water-soluble cap, which further contains a hydrogel plug. When the capsule is swallowed, the water-soluble cap dissolves and exposes the hydrogel plug, which begins to swell. At a predetermined time after ingestion, the hydrogel plug is ejected and the drug is released into the gastrointestinal tract. Multiparticulate dosage forms generally consist of sugar or nonpareil pellets, which are spray coated with a drug, dried, and then spray coated with a second coating composition, which provides controlled release. The second coating composition is typically formed of polymers, which are partially soluble or insoluble in the gastric fluid, wherein the degree of solubility depends on the desired drug release pattern. The doubly coated pellets are placed in a capsule, for swallowing. A capsule may contain pellets of different types and release profiles.
Many of the orally administered drugs are absorbed efficiently in the upper gastrointestinal, tract, the stomach, and the proximal section of the small intestine but barely in the colon [See, Singh at al. J Controlled Release 63 (3), 235 (2000), and U.S. Pat. No. 5,443,843, to Curatolo et al.]. Yet, because the passage of the drug in the upper gastrointestinal tract, the stomach, and the proximal section of the small intestine is relatively fast, generally about 12 hours, the drug bioavailability becomes limited. This implies that a dosage form is operative primarily during that time span. Hence, prolonging the retention time of the drug in the upper sections is of utmost importance for increased bioavailability. [See, Hwang et al. Crit. Rev. Ther. Drug Carrier Syst, 15(3), 243 (1998)].
An answer to the above discussed need may be a long-term gastric retention device, which is taken orally and which is adapted for long-term drug release in the upper gastrointestinal tract. A long-term gastric retention device may be especially useful in cases of drugs taken over long periods, as in instances of chronic diseases and hormonal treatments. It will also simplify treatments that combine different drugs.
The medication that may be considered for long-term gastric retention devices must fit the following criteria: (a) large therapeutic range, so that deviations from the amount of released drug, above or below the predicted level, will not cause significant symptoms; and (b) overdoses will not endanger the patient. Potential drug candidates include: Analgesics, Anxiolytics, Antimigroine drugs, Sedatives, Antipsihotics, Anticonvulsants, Antiparcinsons, Antiallergic drugs, Antidepressants, Antiemetics, Astma-profilactics, Gastric-hypoacidics, Anticonstipation drugs, Intestinal antiinflammatory agents, Antihelmintics, Antianginals, Diuretics, Hypolipidemic agents, Anti-inflammatory drugs, Hormones, Vitamins, and Antibiotics.
Several approaches for long-term gastric-retention device are available:
(A) An anintragastric floating system: this system is designed to float in the gastric fluid. Three major techniques that have been used to generate buoyancy in the gastric fluid are as (follows: (i) A mixture of bicarbonate and gastric fluid generates carbon dioxide, which remains trapped within a matrix of the dosage form. This causes the dosage form to float in the stomach, so as to prolong its residence in the stomach. Similarly, another gas may be produced; (ii) A low-density core system is formed of buoyant materials, such as air, CO2 or gels. It is coated by an outer layer of a dosage form, adapted for controlled release; and (iii) A gel forming hydrophilic polymer, which upon contacting with the gastric fluid forms a gelatinous shell. It may be used to produce a hydrodynamic-balanced system, whose buoyancy is ensured by its dry or hydrophobic core. The gelatinous shell is also responsible for the controlled release of the drug. However, the aforementioned floating devices have a stomach residence time of only a few hours, and their action is dependent upon the amount of food and water in the stomach. Therefore, performance of these devices is non-uniform and difficult to predict.
(B) High-density system is based on sinking the device to the bottom of the stomach. Thus, the device is usually made of heavy materials. Initially, this approach looked promising, but studies have since shown that there is no appreciable gastric retention.
(C) A mucoadhesive system: this adhesive system is able to adhere to the mucous walls of the stomach, and is expected to remain in the stomach, for the duration of the mucous layer turnover. However, it also binds to almost any other material it comes in contact with, for example, gelatin capsules, proteins, and free mucous, in the gastric fluid. Another obstacle is that its adhesiveness is pH-dependent, and higher than normal gastric pH levels reduce the adhesiveness dramatically. Therefore, experimental results were disappointing, and no substantial increase in residence time in the stomach was observed.
(D) A magnetic system: an extracorporeal magnet is placed over the stomach, and small magnetized particles, within the dosage form. Thus, preventing the dosage form from leaving the stomach. Even though some success has been reported, the viability of these systems is in doubt. The doubt arises because the extracorporeal magnet has to be carried and placed very accurately, in order to obtain the desired results. New, more convenient ways to apply a magnetic field have to be found to improve this concept.
(E) An expansible system is based on a sharp dimensional change, in the stomach. Several methods have been proposed for this system: (i) a hydrogel that swells upon contact with the gastric fluid; (ii) an osmotic device that contains salt or sugar, and is surrounded by a semi-permeable membrane; and (iii) a system containing liquid with low boiling point, that turns into gas at body temperature and inflates the device to its desired size, wherein simultaneous with the swelling, a controlled release begins. However, these systems suffer from a slow swelling rate and therefore are not retained in the stomach. Furthermore, the ability to swell to a desired size and the degradation process that follows, still pose substantial challenges.
(F) A superporous, biodegradable, hydrogel system that is based on the swelling of a unique hydrogel system, which is superporous in nature. The system is synthesized by cross-linking polymerization of various vinyl monomers in the presence of gas bubbles formed by chemical reaction of acid and NaHCO2. Compared to other expansible systems, it has a much higher swelling level and swells at a much faster rate than conventional hydrogels, and relatively attaining a desired expanded form in minutes, as opposed to hours. However, the system is mechanically weak, so it breaks down, leading to short residence times in the stomach.
(G) A mechanical, expansible system: this system is based on a mechanical device, which unfolds or extends from an initial, compact size, to an extended form that prevents passage through the gastric pylorus. At present, the mechanically expansible system is the most promising, in the gastric retention field. However, various technical problems, related to its performance are yet to be solved.
Therefore, at present, reliable and efficient long-term gastric retention devices are not available.
Typically, effectiveness of treatment of any medication depends on a patient's adherence to prescription schedule. Low adherence with prescribed treatments is ubiquitous, yet it may undermine the success of a treatment. Typical adherence rates are about 50% for medications and are much lower for lifestyle prescriptions and other more behaviorally demanding regimens [See, Haynes R B, McDonald H P, Garg A X. JAMA 288(22):2880-3 (2002)]. In fact, a Hungarian study reported that one third of hypertension patients took the medication irregularly, despite of the potentially life-threatening implications [See, Rapi J. Ory Hetil 143(34):1979-83 (2002)] Another survey showed that 62.4% patients with familial hypercholesterolemia were not taking their prescribed cholesterol-lowering medication [See, Umans-Eckenhausen M A, Defesche J C, van Dam M J, Kastelein J J. Arch Intern Med 163(1):65-8 (2003).] In fact, missed doses occur more frequently than taking an overdose. [See, De Klerk E, Van Der Heijde D, Landewe R, Van Der Tempel H, Urquhart J, Van Der Linden S. J Rheumatol 30(1):44-54 (2003).]
Conventional methods of improving medication adherence for chronic health problems are complex, labor-intensive, and not very effective. Improving adherence to long-term regimens requires a combination of information about the regimen, counseling about the importance of adherence, advice on how to organize medication regimen in your life, reminders, rewards and recognition for the patient's efforts to follow the regimen, and social support from family and friends. The full benefit of medication is not realized at low levels of adherence. Therefore, more studies and innovative approaches to assist patients to follow prescriptions are needed [See, McDonald H P, Garg A X, Haynes R B. JAMA 288(22):2868-79 (2002)].
Another issue in drug prescription is the efficacy and safety of both new and existing drugs. Efficacy and safety are related factors in a drug's clinical profile. Drug doses are calculated according to a therapeutic window for each drug, which is the range of drug concentration in the blood, ranging between the minimum effective therapeutic concentration and the minimum toxic concentration. The width of the therapeutic window may be measured by a therapeutic index that is the ratio between the median lethal dose and the median effective dose. This is a safety margin for using a specific drug. The wider the index, the safer the drug.
The accepted rule in pharmaceutics is that a drug that has less than a twofold difference between its toxic and effective doses is considered to have a “narrow therapeutic index,” and its use must be carefully monitored. Yet, several clinically important drugs have narrow therapeutic indices. These include anti-AIDS agents like AZT, antibiotics like ciprofloxacin, CNS agents like Levodopa, and anti diabetic agents. Various techniques are available for providing scheduled medication to the patient, for example, chronotheraphy, Dental structure and dental implements, Root Canal, bridge, root canal, dental implants, crown and the like.
Chronotherapy: According to Stehlin [See, Stehlin I., “A Time to Heal: Chronotherapy Tunes In to Body's Rhythms,” US Food and Drug Administration], our body's physiological clock takes its cue from the solar system, affecting blood pressure, blood coagulation, blood flow, and other functions. Several types of physiological cycles may be defined, as follows: (i) ultradian: cycles that are shorter than a day (for example, sleep cycles of about 90 minutes); (ii) circadian: daily cycles (such as sleeping and waking patterns); (iii) infradian: cycles that are longer than 24 hours (for example, monthly menstruation); and (iv) seasonal: for example, a Seasonal Affective Disorder (SAD) that causes depression in susceptible people during the short days of winter.
For instance, the normal lung function under goes circadian changes and reaches a low point in the early morning hours. This dip is particularly pronounced in people with asthma. Therefore, chronotherapy may be especially useful for asthma. It is aimed at getting maximal effect from bronchodilator medications during the early morning hours. For example, the bronchodilator, uniphyl, a long-acting theophylline preparation, manufactured by Purdue Frederick Co. of Norwalk, Corm., and approved by FDA in 1989 may be used for chronotherapy. Taken once a day in the evening, uniphyl causes theophylline blood levels to reach their peak and improve lung function during the early morning hours.
Additionally, according to Stehlin, chronotherapy may be useful in the treatment of cancer, arthritis, hypertension, diabetes, heart-attacks, sexual dysfunction, and eating and sleeping disorders. For example, animal studies suggest that chemotherapy may be more effective and less toxic if cancer drugs are administered at carefully selected times. It appears that there may be different chronobiological cycles for normal cells and tumor cells. Thus, if administration of cancer drugs is timed with the chronobiological cycles of tumor cells, it will be more effective against the cancer and less toxic to normal tissues.
Furthermore, chronobiological patterns have been observed with arthritis pain. People suffering from osteoarthritis, the most common form of the disease, tend to be in pain at night. But for people with rheumatoid arthritis, the pain usually peaks in the morning. When using chronotherapy for arthritis, both nonsteroidal anti-inflammatory drugs and corticosteroids may be timed to ensure that the highest blood levels of the drug coincide with the times of peak pain.
Techniques exist that attach devices either in the mouth or in other parts of the body to control drug release. For example, the device may be attached to or placed around teeth or implanted into the gum.
Dental structure and dental implements: the following is a brief overview of a tooth structure and of known techniques for dental repair and reconstruction. With reference to FIG. 1, a typical cross-sectional view of a tooth 100 is shown. As seen in the FIG, the basic parts of a tooth are: a crown 102, the portion of tooth above a gum 104, and a root or roots 106, which anchor the tooth in a jawbone. A pulp 108 is arranged within a pulp chamber 110 and within a root canal or root canals 112.
Crown 102 is formed of an inner structure of dentine 116 and an external layer of enamel 114, which defines a chewing surface 118. There may be one, two, or more roots 106. Each root has an external layer of cement 120, inner structure of dentine 116, and one root canal 112. Pulp 108 is formed of tiny blood vessels, which carry nutrients to the tooth, and nerves, which give feeling (senses) to the tooth. The blood vessels and the nerves enter root canals 112 via accessory canals 122 and root-end openings 124.
Tooth 100 may define a cylindrical coordinate system of a longitudinal axis ‘x’, and a radius ‘r’. A coronal or incisal end 126 may be defined as the end above gum 104 and an apical end 128 may be defined as the end below the gum.
Various intra oral devices and dental reconstruction and repair methods are discussed in conjunction with FIGS. 2A to 7C, here in below.
A root canal treatment may be required when the pulp is diseased or injured and dies. Common causes of pulp death are a deep cavity, a cracked filling, or a cracked tooth. Bacteria then invade the tooth and infect the pulp. The inflammation and infection may spread down the root canal, often causing sensitivity to hot or cold foods and resulting into pain. Root canal treatment involves removing the diseased pulp. After this, cleaning and sealing the pulp chamber and root canals. Lastly, filling or restoring the crown. The steps in root canal therapy are illustrated in FIGS. 2A to 2G.
FIGS. 2A, 2B, and 2C illustrate a root canal treatment in which crown 102 was not severely damaged. As seen in FIG. 2A, an opening 202 is made, generally through crown 102 and dentine 116, into the pulp chamber 110. Pulp 108 (FIG. 1) is then, removed with a tiny file (not shown). Further, pulp chamber 110 and root canals 112 are cleaned and shaped to a form that may be filled.
As seen in FIG. 2B, medications 204 may be applied to pulp chamber 110, and root canals 112, for a period of about two weeks, to disinfect them. A temporary filling 206 may be placed in crown opening 202 to protect the tooth between dental visits.
As seen in FIG. 2C, after removing medications 204 and temporary filling 206 of FIG. 2B, pulp chamber 110 and root canals 112 are cleaned and filled with a permanent filling 208, and chewing surface 118 is restored.
FIGS. 2D-2G illustrate situations in which crown 102 (FIG. 1) was severely damaged. As seen in FIG. 2D, remnants of crown 102 are removed, and root canals 112 are cleaned and shaped as discussed above.
As seen in FIG. 2E, medications 204 may be applied to root canals 112, for a period of about two weeks, to disinfect the root canals. A sealing layer 207 may then be applied over the exposed dentine, to protect it until the next dental visit.
As seen in FIG. 2F, after removing medications 204 of FIG. 2E, root canals 112 are cleaned and filled with permanent filling 208. A core 209 of permanent filling 208 is then constructed over the roots, to restore the crown, and a mold (not shown) is taken of the remaining tooth structure and core 209. A temporary structure 210 is then placed over the remaining tooth structure and core 209.
As seen in FIG. 2G, a permanent, enamel-like structure 212 is prepared from the mold, and placed over core 209.
On the other hand, when teeth are lost, replacement options include bridges implant and dentures. A bridge may be used to fill a gap of up to four teeth, where there are healthy natural teeth on either side of the gap. FIGS. 3A-3F illustrate an application of a three-unit bridge 300 between two healthy teeth 302 and 304. As seen in FIGS. 3A-3B, the dentist will prepare teeth 302 and 304 on either side of the gap by removing portions of the enamel and dentin, leaving stumps 306 and 308. Impressions or molds of stumps 306 and 308 and the gap between them are taken for the construction of the bridge. In the meantime, a temporary bridge is applied to protect the exposed stumps and provisionally restore the missing teeth.
As seen in FIGS. 3C and 3D, the dentist then fits bridge 300, where the bridge 300 includes a prosthetic tooth crown 310, over stumps 306 and 308. If the fit is good, the dentist cements bridge 300 into place, restoring function to the area.
FIGS. 3E-3F illustrate an alternative technique: a bridge 312 may be formed including a prosthetic tooth crown 210 and anchors 314, such that the anchors 314 are adapted to clamp onto healthy teeth 302 and 304. Unlike bridge 300 of FIGS. 3C-3D, which is cemented into place, bridge 312 may be removed, for example, for cleaning.
As an alternative to a bridge, a dental-implant-and-prosthetic-tooth-crown 400 may be used. As seen in FIGS. 4A-4C, dental-implant-and-prosthetic-tooth-crown 400 includes, for example, a dental implant or fixture 402, surgically implanted into the bone that grows around the tooth 400. Once dental implant 402 is anchored into the bone, a stump 404 is mounted on it and prepared to accept prosthetic tooth crown 310.
In a situation where several teeth are missing, dentures 500 may be used, containing a plurality of prosthetic tooth crowns 310, as seen in FIGS. 5A-5C. It is possible to get either full dentures, of all the teeth, as seen in FIG. 5A, or partial dentures, of fewer teeth, as seen in FIG. 5B. Full dentures are form-fitted to the gum ridges, creating an adhesive effect that keeps them in place. Partial dentures may be adapted to fit around the natural teeth, to help them stay in place. Additionally, as seen in FIG. 5C, a dental implant post 402 may be used to further secure the dentures.
In some cases, the root of the tooth is intact, but its upper portion is severely decayed or broken. An artificial crown may then be placed on the tooth, as seen in FIGS. 6A-6C. FIG. 6A illustrates a broken tooth 602. As seen in FIG. 6B, it is prepared by removing a portion of the enamel and dentin, and exposing a stump 604, As seen in FIG. 6C, a crown 606 is then cemented over stump 604, hence, restoring the chewing surface.
Braces are other known orthodontics dental devices. FIG. 7A illustrates braces 700 that include molar bands 702, arch wires 704, and brackets 706. FIG. 7B illustrates braces 710, which includes a metal or plastic plate 712, and wires 714 and 716. The metal plate 12 is adapted to fit against the roof of the mouth. FIG. 7C illustrates invisible braces 720. In general, the braces of FIGS. 7A-7C may be easily removed, for example, for cleaning.
Various slow-releasing devices to be attached to or placed around teeth or implanted into the gum are available, for example U.S. Pat. No. 3,624,909, U.S. Pat. No. 3,688,406, U.S. Pat. No. 4,020,558, U.S. Pat. No. 4,175,326,U.S. Pat. No. 4,681,544, U.S. Pat. No. 4,685,883, U.S. Pat. No. 4,837,030, U.S. Pat. No. 4,919,939, U.S. Pat. No. 6,264,974, and U.S. Pat. No. 6,399,610. The devices mentioned above and those quoted here in after deliver a medication into the oral cavity, but these devices lack a controlled rate of drug delivery for extended time periods which is of utmost importance in the prevention and treatment of the heretofore mentioned diseases and conditions.
U.S. Pat. No. 4,020,558, to Cournut, et al., entitled “Buccal implant for administering solubilizable products,” describes a buccal implant constituting at least one plate of small thickness formed of a material containing solubilizable substances. The plate is fastened to the teeth and maintained in close proximity to the gum in order to pass the solubilizable substances into the saliva.
U.S. Pat. No. 4,837,030, to Valorose, Jr., et al., entitled “Novel controlled release formulations of tetracycline compounds,” describes pharmaceutical compositions comprising spherical granules including thereon or therein a 7- or 9-alkylamino-6-deoxy-6-demethyltetracycline or an acid-addition salt thereof blended with at least one excipient adapted to control the rate of drug release in the stomach and in the intestine in order not to produce nausea or dizziness upon oral administration during antibacterial therapy. The invention discloses an orally administrable pharmaceutical composition comprising beads coated with an ultra-thin layer of a polymer that erodes under gastric conditions. When suspended in water, more than 90% of the pharmaceutical agent is released from the composition in between 20 to 90 minutes. U.S. Pat. No. 4,919,939, to Baker, entitled “Periodontal disease treatment system,” describes a controlled release drug delivery system for placement in the periodontal pocket, gingival sulcus, tooth socket, wound or other cavity within the mouth. The system incorporates drug-containing micro-particles in a fluid carrier medium, and is effective in the environment of use for up to 30 days. The patent discloses a controlled release drug delivery system comprising a polymeric matrix, which dissolves, releasing the drug contained therein within 10 to 18 hours, upon the action of the saliva.
U.S. Pat. No. 6,143,948, to Leitao, et al., entitled “Device for incorporation and release of biologically active agents,” describes an implantable device coated with a layer of calcium phosphate and optionally one or more biologically active substances such as growth factors, lipids, (lipo) polysaccharides, hormones, proteins, antibiotics or cytostatics. The implant may be used for biomedical use, i.e. as a bone substitute, a joint prosthesis, a dental implant (prosthodontics), a maxillofacial implant, and the like.
U.S. Pat. No. 6,264,974, to Madhat, entitled “Buccal and sublingual administration of physostigmine”, describes Physostigmine administered buccally or sublingually in non-sustained release dosage form, providing prolonged blood levels. This active agent is physically compounded with materials of some or all of classes of ingredients that function as pH controls, preservative agents, viscosity control agents, absorption enhancers, stabilizing agents, solvents, and carrier vehicles. This compounding will produce a pharmaceutical composition in the form of a liquid, tablet, gel, patch or lozenge for administration of the active agent, Physostigmine, by absorption through the buccal or sublingual mucosa of the patient.
U.S. Pat. No. 6,399,610, to Kurkela, et al., entitled “Transmucosal formulations of levosimendan,” describes a method of administering transmucosally, particularly to oral or nasal mucosa, levosimendan or a pharmaceutically acceptable salt thereof to a patient. The method comprises contacting an intact mucous membrane with a source of levosimendan, and maintaining said source with said mucous membrane for a sufficient time period to deliver levosimendan to the patient.
Other patent disclose implanted devices, either in the mouth or in other parts of the body, including diverse mechanisms to control drug release. U.S. Pat. No. 4,252,525 to Child, entitled “Dental implant,” describes a tooth prosthesis located in a mandible tooth socket having a root supporting a crown. An elastic body of ethylene vinyl acetate (EVA) copolymer surrounds and is bonded to the stem. The fabric has a pyrolite carbon outer skin. The upper edge of the fabric is spaced from the crown and head whereby the elastic body allows limited movement of the crown relative to the fabric. Ionic silver is released from the bands, which provides anti-bacterial action. In one form, a silver wire contained in the root and connected to a band and a source of direct current releases ionic silver into the surrounding tissue. In another form, the root, crown, and body have passages for accommodating drug materials and silver compounds.
U.S. Pat. No. 4,871,351, to Feingold, entitled “Implantable medication infusion system,” describes an implantable medication delivery system comprising an implantable unit with a refillable reservoir, a catheter connected thereto, and a pumping mechanism activated by a microcomputer or microprocessor for pumping medication from the reservoir through the catheter into the body. The implantable medication unit receives information and control commands via a telemetry link from an external controller unit having a microprocessor. The external controller receives feedback in the form of intermittent sampling of blood using enzyme strips and a reflectance meter and/or additional sensor(s) which measure(s) physiological parameter(s) such as heart rate or blood pressure or temperature or skin resistivity. The feedback information is processed by the external unit in accordance with a mathematical model of the patient and the relevant parameters are transmitted to the implanted unit which adjusts its delivery profile according to a prescribed algorithm. The external unit may also detect an alarm condition and take appropriate steps, e.g. abort infusion.
U.S. Pat. No. 5,090,903, to Taylor, et al., entitled “Dental prosthesis with controlled fluid dispensing means,” describes a system for automatically and progressively dispensing fluids into an individual's mouth comprising a dental prostheses such as a bridge having an interior cavity with a plurality of chambers defined therein. A first passageway communicates between the inner chamber and the interior of the mouth for progressive delivery of fluid from the chamber into the mouth. A second passageway communicates between the outer chamber and the outer surface of the bridge and functions as a vent. The walls, openings, and passageways are positioned and oriented such that fluid is dispensed into the mouth progressively from the inner chamber during waking hours when the wearer is in a standing or upright position and is not dispensed during the night time or sleeping hours when the wearer is in an inclined or lying position. The wall holes are positioned such that the inner chamber of the cavity is refilled during sleeping hours for subsequent dispensing when the wearer wakes and arises.
U.S. Pat. No. 5,196,002, to Hanover, et al., entitled “Implantable drug delivery system with piston actuation,” describes an implantable drug delivery system including a housing having a base end and a discharge end, for holding drug solution at the discharge end, a valve disposed at the discharge end to allow a drug solution to flow from inside the housing, through the valve and out of the housing when solution pressure is applied to the valve, a piston slidably disposed in the housing to slide between the base end and discharge end to force solution toward the discharge end and out the valve, and a spring disposed in the housing between the piston and the base end thereof for urging the piston toward the discharge end. A timing circuit is disposed to supply release signals sequentially, and as a result the piston is allowed to move toward the discharge end of the housing to thereby discharge or bolus of drug solution from the housing, until the next shortest unreleased tether stops further movement of the piston.
U.S. Pat. No. 5,433,952, to Sipos, entitled “Intraoral medicament-releasing device,” describes controlled rate-release devices for releasing a pharmaceutically active agent into the oral cavity by the dissolving action of the saliva. U.S. Pat. No. 5,558,640, to Pfeiler, et al., entitled “System for infusion of medicine into the body of a patient,” describes a system for infusing medicine into the body of a patient including an implantable infusion apparatus containing a dosing unit with a reservoir for the medicine and a medicine delivery pump for pumping doses of the medicine from the reservoir into the patient. The infusion apparatus also includes a sensor for sensing a parameter of the patient for controlling the dosing of medicine according to the sensed parameter. The dosing unit and the sensor are galvanically separable and are each provided with separate telemetry communication units for communication with an external programmer/controller. The external programmer/controller includes telemetry communication units for selectable communication with the dosing unit or the sensor or both simultaneously. The telemetry communication units of the external programmer/controller, the dosing unit and the sensor are constructed for bi-directional communication between the external controller and each one of the dosing unit and the sensor.
U.S. Pat. No. 5,584,688, to Sakuma, et al., entitled “Medicine injection device,” describes a medicine injection device capable of continuously administrating a medicine to the body of a patient over a long period of time while keeping the patient from being restrained during administration. The medicine injection device includes a medicine container and at least one medicine passage each arranged in at least one of a root and a crown, so that a medicine stored in the medicine container is administrated through the medicine passage to the body of a patient.
U.S. Pat. No. 5,614,223, to Sipos, entitled, “Intraoral medicament-releasing device,” describes controlled rate-release devices for releasing a pharmaceutically active agent into the oral cavity by the dissolving action of the saliva, a process of preparing such devices and methods of preventing/treating conditions/diseases in a mammal by delivering a pharmaceutically active substance into the oral cavity.
U.S. Pat. No. 5,686,094, to Acharya, entitled, “Controlled release formulations for the treatment of xerostomia,” describes controlled or sustained dosage forms, and in particular certain polymeric matrices or complexes which are suitable for achieving controlled or sustained delivery of an active composition. The compositions are especially useful for local, parenteral, buccal, gingival, and oral controlled release of active compositions, such as pharmaceuticals, and take the form of granules, encapsulated capsules, tablets, chewable gums, ingestible and implantable boluses, candies, lolipops, pourable liquids, gels, suppositories and the like.
U.S. Pat. No. 5,869,096, to Barclay, et al., entitled “Oral osmotic device with hydrogel driving member,” describes an osmotic device for delivering a drug, such as an anti-fungal, into the mouth of a human patient is disclosed. The device comprises a wall surrounding a compartment housing a layer of an agent that is insoluble to very soluble in aqueous biological fluids, e.g., saliva, and a layer of a fluid swellable, hydrophilic polymer. A passageway in the wall connects the agent with the exterior of the device. The wall is permeable to the passage of aqueous biological fluid but substantially impermeable to the passage of the hydrophilic polymer.
U.S. Pat. No. 7,699,834, to Hood, et al., entitled “Method and system for control of osmotic pump device,” describes a system including a remotely controlled osmotic pump device and associated controller. According to some embodiments, an osmotic pump device is placed in an environment in order to pump a material into the environment or into an additional fluid handling structure within the osmotic pump device. In selected embodiments, a magnetic field, an electric field, or electromagnetic control signal may be used.
US Patent Application Publication No. 20060115785, to Li, et al., entitled “Systems and methods for intra-oral drug delivery,” describes systems and methods for intra-oral delivery of drugs. For dental diseases, the system is placed so that release of the therapeutic agent occurs in the immediate vicinity of the disease process.
US Patent Application Publication No. 20040147906, to Voyiazis, et al., entitled “Implantable interface system,” describes an oral implant including one or more chambers capable of containing materials delivered and/or receiving materials extracted by the implant. Micro- and nano-mechanical and electro-mechanical components, such as microfluidic pumps, perform the mechanics of the delivery and/or extraction of material via the oral implant. Communications means, including wireless communications, associated with the oral implant allow for remote control of the implant and/or remote reporting of information associated with the implant, such as test results.
US Patent Application Publication No. 20020133120, to Yeh, entitled “Light, thin, and flexible medication infusion apparatuses attachable to user's skin and watch type monitor and controller,” describes apparatuses having multiple reservoir cells, a pump, a pump controller, one or more batteries on a flexible pad so that the apparatuses may be adhesive to the user's skin as a big and thick Band-Aid.
U.S. Patent Application Publication No. 20040147906, to Voyiazis et al., entitled “Implantable Interface System”, describes an oral implant that may include a micro-pump or nano-pump for extracting or delivering material to the body of the patient.
In the light of above discussion, systems, methods and devices are desired that provide for controlled rate of drug release for extended period of times to cure chronic diseases.